A Type 2 Diabetes-Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus.
Diabetes
; 66(9): 2521-2530, 2017 09.
Article
in En
| MEDLINE
| ID: mdl-28684635
ABSTRACT
Molecular mechanisms remain unknown for most type 2 diabetes genome-wide association study identified loci. Variants associated with type 2 diabetes and fasting glucose levels reside in introns of ADCY5, a gene that encodes adenylate cyclase 5. Adenylate cyclase 5 catalyzes the production of cyclic AMP, which is a second messenger molecule involved in cell signaling and pancreatic ß-cell insulin secretion. We demonstrated that type 2 diabetes risk alleles are associated with decreased ADCY5 expression in human islets and examined candidate variants for regulatory function. rs11708067 overlaps a predicted enhancer region in pancreatic islets. The type 2 diabetes risk rs11708067-A allele showed fewer H3K27ac ChIP-seq reads in human islets, lower transcriptional activity in reporter assays in rodent ß-cells (rat 832/13 and mouse MIN6), and increased nuclear protein binding compared with the rs11708067-G allele. Homozygous deletion of the orthologous enhancer region in 832/13 cells resulted in a 64% reduction in expression level of Adcy5, but not adjacent gene Sec22a, and a 39% reduction in insulin secretion. Together, these data suggest that rs11708067-A risk allele contributes to type 2 diabetes by disrupting an islet enhancer, which results in reduced ADCY5 expression and impaired insulin secretion.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Genetic Variation
/
Adenylyl Cyclases
/
Gene Expression Regulation
/
Islets of Langerhans
/
Diabetes Mellitus, Type 2
/
Genome-Wide Association Study
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Diabetes
Year:
2017
Type:
Article
Affiliation country:
New Caledonia